Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents - Volume 5, Issue 3, 2005

The cause of osteoarthritis (OA) - the most prevalent joint disease - remains unknown and no cure has been identified. The OA patient seeks help because of symptoms (primarily pain) and impaired function. However, the underlying mechanisms resulting in pain or structural damage that contribute to impairment of joint function are not completely understood. Currently available drug treatments are palliative at best. Although they are reported to offer some clinical benefit, few, if any, have been extensively investigated by well-validated, evidence-based studies. They often fail to control symptoms in the long term, and do little to address the underlying causes of disease progression. While OA pain is still an unmet medical need, alleviating pain alone may lead to further joint damage, because pain may have a protective role in the affected joint by causing a reduction in weight bearing. Moreover, there is a poor correlation between disease severity and symptoms. OA disease progression, regardless of the pathogenesis, involves anabolic and catabolic changes in multiple components of the joint, including cartilage, subchondral bone, synovium and the joint capsule. Thus, comprehensive treatment for OA should aim for long-term improvement in all dimensions, including palliating symptoms, alleviating pain, inhibiting tissue destruction, promoting repair and regeneration, and improving joint function. The ultimate objective is to treat the OA patient as a whole. This paper reviews the available therapeutic options for OA and discusses the prospects for developing a comprehensive treatment(s) for osteoarthritic and damaged joints.

Aspirin and conventional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely prescribed for the treatment of musculoskeletal disorders with a major dose limiting gastrointestinal toxicity. However the discovery of inducible second isozyme of cyclooxygenase-2 (COX-2) opened up a new era in therapeutics. The selective COX-2 inhibitors have emerged as a class of compounds for the treatment of inflammatory disorders based on the molecular knowledge, characterization of two distinctive isozymes namely the constitutive cytoprotective cycloooxygenase-1 (COX-1) and the inducible inflammatory COX-2.The current hypothesis is that anti-inflammatory effects are mediated through the inhibition of COX-2 derived inflammatory prostaglandins (PGs), on the contrary the gastrointestinal adverse effects were due to inhibition of constitutive COX-1. The rationale approach is that the selective COX-2 inhibitors may provide a significantly improved gastrointestinal risk-benefit ratio over NSAIDs. However, the withdrawal of Vioxx by Merck & Co from worldwide markets has triggered a debate on the safety of this class as it was observed, that selective inhibition of COX-2 could lead to an imbalance of normal homeostasis resulting in potential cardiovascular risks. Evidence is emerging that the constitutively expressed COX-2 has important role in gastric mucosal protection, renal and the cardiovascular homeostasis. Suppression of endothelial prostacyclin (PGI2) by highly selective COX-2 inhibitors could lead to myocardial infarction and stroke implicating that COX-2 may have a pivotal role under certain physiological conditions.

Oxidant stress as a result of increased production of reactive oxygen species (ROS) or a reduction in the body's endogenous antioxidant defense system is a hallmark of chronic inflammatory diseases including rheumatoid arthritis (RA). A primary source of ROS in RA is leukocytes (i.e. activated macrophages, neutrophils, mast cells and lymphocytes) that are recruited to, and that accumulate within, the synovium. ROS and reactive nitrogen species (RNS) can contribute to the pathogenesis of RA in a variety of ways including: induction of membrane oxidation and instability, irreversible damage to proteins and DNA, cartilage damage and induction of bone resorption. In addition, it has recently been appreciated that ROS/RNS can also modulate a variety of signaling events that control gene expression and effect cellular processes that participate in chronic inflammation. These include effects on vascular tone, cell growth and proliferation and induction of pro-inflammatory genes. Consistent with a role for oxidant stress in the pathogenesis of RA, a number of preclinical and clinical studies have correlated increases in markers of oxidative stress and lower levels of the body's natural antioxidants with disease severity. Accordingly, a variety of methods aimed at reducing ROS production, scavenging ROS or restoring the antioxidant balance have been tested with some success in experimental models of RA and in clinical trials. Although considerable data supports the notion that antioxidant-based drugs could prove beneficial in the treatment of RA, very few have been evaluated clinically and to date none have demonstrated clinical proof-ofconcept in Phase II clinical studies.

The population effected by rheumatoid arthritis (RA) and osteoarthritis (OA) is increasing worldwide. There is also a dramatic progress in the understanding of the etiology and pathophysiology of these diseases and the use of biological disease modifying anti-rheumatic drugs (DMARD) for the treatment of RA. High costs of biological DMARDs and the lack of oral drugs are the biggest limitations to RA therapy. In addition, there are currently no orally bioavailable disease-modifying OA drugs (DMOADs) in market. While inflammation continues to be the primary target for drug discovery in RA, inhibiting degradative pathways and promoting anabolic pathways may have potential in OA. Synthetic disease modifying agents with better efficacy, lesser side effects and affordability to use in a chronic disease is the unmet pharmacological need. The present review summarizes the key molecular pathways contributing to the disease and emerging drugs that prevent these pathways.

The innate and adaptive immune responses are closely linked and mutually reinforcing. The type of adaptive immune response is strongly influenced by the cytokines produced by innate immune cells. Interleukin-12 (IL-12) plays a key role in linking innate immunity to an adaptive T helper-1 (Th1) response against pathogens and tumor cells, thereby counteracting an imbalanced Th2 immune response. These properties make IL-12 a powerfull candidate to revert the Th2 dominance into a polarized immune response, e.g., in the tumor environment. Due to the heterodimeric structure, recombinant IL-12 fusion proteins provide the potential to create agonistic as well as antagonistic derivatives. The latter IL-12 derivatives block IL-12 activity by competitive binding to the receptor, e.g., to repress chronic inflammatory processes. Here we discuss functional properties of recombinant IL-12 constructs for use in immunotherapy, particularly (i) the agonistically acting IL-12(p40-p35) protein designed to boost anti-tumor immunity by reverting Th2 dominance and by increasing the effector functions of tumor infiltrating T- and NK-cells, and (ii) the antagonistically acting IL-12(p40)2 dimer protein designed to block IL-12 functions in chronic inflammatory diseases. Despite their limitations, both types of recombinant IL-12 derivatives have significant implications for the immunotherapy of malignant diseases as well as of bowel disease.

Acromegaly is a relatively rare debilitating disease caused by hypersecretion of growth hormone (GH). Despite a multimodality approach involving surgery, radiation, dopamine agonists and somatostatin agonists the management of acromegaly in some patients has remained a challenge. Although, octreotide and lanreotide are the mainstay for medical therapy in acromegaly, their relatively short biological half-life, pharmacokinetic profiles and side effects emphasize the need for a new generation of somatostatin analogs with improved therapeutic index. The antisecretory activity of somatostatin is mediated by high affinity somatostatin receptors (which belong to five subtypes) on pituitary adenomas. The suppression of GH secretion by somatostatin is mediated primarily by sst2 and sst5, via inhibition of cAMP and intracellular calcium levels. Additionally, the inhibition of exocytosis and cell proliferation by ssts also contributes to the antisecretory activity of somatostatin. Sst2 and sst5 are expressed in almost all GH-secreting adenomas. The present review summarizes the in vitro and in vivo GH-inhibitory activity of novel somatostatin agonists and their potential applications in the therapy of acromegaly. The signaling networks underlying somatostatin receptor subtypes particularly sst2, sst5 and sst1 in mediating the antisecretory activity of somatostatin agonists have been discussed. A brief summary of the clinical efficacy of currently available somatostatin agonists in acromegaly patients is also presented. Novel somatostatin analogs like PTR3173, ASS-52, SOM230, KE108 and bispecific agonists (analogs targeting more than one cellular receptor) like BIM-23244 and BIM-23A387 represent a new generation of GH-inhibitory agents, which may lead to improved therapeutic strategies in acromegaly.

The traditional view of the adipocyte as a passive receptacle for storage and combustion of triacylglycerol is undergoing rapid change. It is now recognized that a variety of adipocyte and adipose stromal cell derived bioactive peptides, collectively termed “adipokines”, act both locally and distally through autocrine, paracrine and endocrine effects. Alteration of adipose tissue mass in obesity increases the production of most adipose secreted factors; therefore white adipose tissue could play a key role in multiple metabolic disorders and in the increased risk of cardiovascular disease associated with obesity. In fact, increased activity of tumor necrosis factor and interleukin 6 are involved in the development of the insulin resistance present in obesity. In contrast, other adipokines, like adiponectin and leptin, are insulin sparing through stimulatory affects on the beta oxidation of fatty acids in skeletal muscle. Other adipokine have been implicated in hypertension (angiotensinogen) and impaired fibrinolysis (PAI-1). The role of resistin is poorly understood: this protein seems surely implicated in insulin resistance in rats, but probably not in humans. Reduction of adipose tissue mass, through weight reduction in association with exercise, has been shown to improve the adipokines production (reduction in TNF-α and IL-6, increase in adiponectin) while the thiazolinedione drugs increase endogenous adiponectin production. These results support the idea that the development of new drug targeting adipokines might represent a promising therapeutic approach to protect obese patients from atherosclerosis. This paper will review the function and the regulation of adipocytokines in order to understand how obesity may contribute to metabolic syndrome.